Pacritinib: Phase 3 PACIFICA Trial Dr. Mascarenhas ASH 2022

Pacritinib: Phase 3 PACIFICA Trial Dr. Mascarenhas ASH 2022

By John Mascarenhas, MD

What is the study of Pacritinib in the PACIFICA Clinical Trial in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis? The study we’re talking about is the PACIFICA study, which is a phase 3 randomized study of Pacritinib. The JAK2/IRAK1/ACVR1, ACVR1 inhibitor. Compared to best available therapy in patients who have platelet counts, myelofibrosis, patients who have platelet counts less than 50,000. And this is a clinical trial post-marketing, so the drug is now approved in the US with a label for patients with myelofibrosis and platelet count less than 50,000. And that was based off of data analysis that came out of the PERSIST 2 study, which included patients up to a hundred thousand platelet count. The PACIFICA (Pacritinib trial) really is aimed at confirming the efficacy that we saw in the phase 3 PERSIST-2 study in terms of spleen volume response and symptom improvement, as well as confirming toxicity profile (adverse events) and tolerability.

And perhaps even documenting clinical improvement in terms of anemia, which we saw in 25% of treated patients with extreme thrombocytes, in the PERSIST-2 study. So the PACIFICA study, it’s an ongoing study. It’s still accruing patients, it’s a global study. It’s completed accrual in the us and it is now accruing XUS. And it is looking, aiming to, ultimately enroll 399 patients who have DIPSS intermediate or higher risk disease. And as I said, a platelet count less than 50,000, and are JAK inhibitor naive. Now the key part here is patients could have seen prior JAK inhibitor therapy up to 270 days of low dose ruxolitinib or up to 90 days of any JAK2 inhibitor monotherapy or treatment with more than one JAK inhibitor would be prohibited. So you can see a limited amount of low dose JAK inhibitor, but not other JAK inhibitors or JAK inhibitor based therapies. And the control arm (control group) in this randomized study would include low-dose ruxolitinib, so that’s 5 milligrams once a day or twice a day, hydroxyurea, danazol or corticosteroids. And it is randomized in a two to one fashion to pacritinib and physician choice. And the co-primary endpoint is spleen volume reduction of 35% or greater plus TSS 50% or greater at 24 weeks with key secondary endpoints including patient global impression of change at 24 weeks, overall survival and safety.

Common Questions You Are Asked About the Pacritinib Trial?

The most common questions that are asked about the study is why is the platelet count restricted to 50,000? Since there is data from PERSIST-2 and PERSIST-1 indicating activity of Pacritinib in patients with moderate thrombocytopenia, 50 to a 100,000. This was a decision that was made ultimately by the FDA as it was seen as an unmet need, an urgent unmet need to have a JAK inhibitor therapy option for patients with less than 50,000, where the labels for Ruxolitinib and Pacritinib currently exclude those patients. Although in, in my opinion, if you have patients (with Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis) who have platelet counts in the 75,000 range again, that would be off-label, I think those patients are also appropriate for Pacritinib in which, PERSIST-2 to phase 3 data to support that. And then the NCCN does endorse the use of Pacritinib as a second line agent, irrespective of baseline platelet counts. So I think there are various areas where Pacritinib can be used.

And the other question I often get is, what makes Pacritinib different or unique? Is it just another JAK2 inhibitor? I would say not just another JAK2 inhibitor, it is a JAK2 inhibitor. It’s a selective JAK2 inhibitor. That’s one distinction between Pacritinib and Ruxolitinib, which is an equally potent JAK1/2 inhibitor.

It is FLT3 inhibitor like Pacritinib, but unlike Pacritinib and Ruxolitinib it is an IRAK-1 inhibitor, anIL-1 receptor associated kinase inhibitor, which is part of a signaling pathway that is key to NF-kappaB, which has been shown to be upregulated in patients with myelofibrosis and is a therapeutic target and Ruxolitinib does not extinguish NF-kappaB activity, and it’s likely that the dual action of JAK2 inhibition IRAK-1 inhibition allows for dosing in cytopenic patients. And potentially also may underlie in addition to its a ACVR1.

Inhibition property anemia responses, which are seen in 25% of patients treated with Pacritinib. So it is an next generation JAK inhibitor with additional cytokines profiles of IRAK1 and ACVR1 that likely enable better enable this drug to be given at a full dose and maintain at a full dose, even in the face of significant thrombocytopenia. And also result in anemia responses in a fraction of patients.

Will The Pacritinib Data Provide Clinical Benefit?

I think ultimately the results of the PACIFICA (Pacritinib) study should hopefully and ideally provide additional confidence to the efficacy that we saw in PERSIST-2 and and confirm safety. This drug does not have a signal of increased cardiovascular risk factors compared to BAT and even Ruxolitinib directly in a one-to-one comparison from a sub analysis of PERSIST-2 there may be an increased bleeding risk that is independent of the degree of protopia, but even that is not entirely clear. So I think the benefit of the PACIFICA study will be to further confirm and provide confidence in the safety profile of Pacritinib, which again, has really been mostly tested in patients with cytopenic myelofibrosis, a phenotype that is typified by low blood counts (Eg. red blood cell counts) aggressive disease course, shortened survival and is likely more prone to having complications in poor outcomes. So sometimes it’s difficult to fully tease out what is disease versus therapy related. And hopefully the PACIFICA will provide that degree of confidence going forward.

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What is the Next Step for The Pacritinib PACIFICA Clinical Trial ?

I think we need to finish it and we need to finish the Pacific PACIFICA study and of course, that  it’s a challenging study to complete. And obviously in the US accrual is stopped because the drug is commercially available and, clinicians are more apt to reach for the commercial option, then to enroll their patients on a randomized study, which is understandable.

In this era of covid in the pandemic and getting patients with low platelets into research centers for enrollment is challenging. But it continues and I’m confident they will they will complete the study and it will provide additional valuable information and particularly information that we will never have from the PERSIST studies because they were stopped prematurely due to a full clinical hold by the FDA (United States Government Health Agency). And that’s survival. So the PACIFICA trial will hopefully provide us survival data, which is missing from the PERSIST studies.

5 Key Takeaways on the PACIFICA Trial

1. This is a randomized clinical trial (study ID PAC203 North America; PAC303 ex-North America) compares 200 mg twice daily pacritinib versus P/C treatment in individuals with MF and severe thrombocytopenia (platelet count 50,000/L).

2. A total of 399 myelofibrosis patients will be enrolled and randomized 2:1 to either pacritinib (about 266 individuals) or P/C treatment (approximately 133 patients gave informed consent).

3. Spleen volume reduction [Time Frame: From baseline at 24 weeks]. To evaluate the efficacy of pacritinib with that of physician’s choice (P/C) medication, as determined by the proportion of patients attaining a 35% reduction in spleen volume (SVR) as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scans.

Key Data Points From The Pacritinib Study

I think that collectively the key takeaway from the Pacritinib program is an alternative JAK2 inhibitor with IRAK-1 and ACVR1 inhibition. That provides spleen and symptom benefit to patients with cytopenias and challenges in administration of currently available JAK inhibitors. And this really broadens the the benefit of JAK inhibitors to patients beyond the proliferative phenotype, which is typically who’s been more likely to gain benefit from this class of drugs. I think it also offers the potential to explore combination approaches with Pacritinib as it is less myelosuppressive. So it may be an ideal combinatorial partner for future combination therapy approaches that are likely to have deeper more meaningful responses than JAK inhibitor monotherapy.

Final Thoughts For the Pacritinib Trial

I think just to point out that patients myelofibrosis is a complex disease with a lot of clinical variability of heterogeneity, both in presentation and course. It is molecularly complicated, and the field is moving forward with multiple different JAK inhibitor options, even combination options such as combination JAK inhibitor plus Pacritinib, the BET inhibitor Navitoclax, the BCL2 inhibitor Parsaclisib, the PI3K kinase inhibitor.

And then salvage therapies like a metals stat that kinase inhibitor that all look to achieve improvements in the progressive disease state (disease progression) and even potentially prolongation of survival. And there are multiple therapies that are being evaluated to address anemia. So it’s an exciting time to be in clinical research in this area.

But a complicated time to practice as there are a lot of different options and emerging options. So I would strongly urge clinicians in the community to consider referral and second opinion. Tertiary centers and centers of excellence in MF for consultation and evaluation for potential trial options.

And importantly for consideration of hematopoietic stem cell transplantation, which remains the only modality that offers the potential for cure which is for a minority of patients, but it’s still probably underutilized.

John Mascarenhas, MD – About The Author, Credentials, and Affiliations

Associate Professor of Medicine and a doctor of Medical Oncology at the Icahn School of Medicine at Mount Sinai (ISMMS) and a member of the Tisch Cancer Institute is Dr. John Mascarenhas. Dr. Mascarenhas is the Director of the Adult Leukemia Program and the Leader of Clinical Investigation for the Myeloproliferative Disorders Program at Mount Sinai, where he works under the supervision of Dr. Ronald Hoffman. As a clinical investigator in malignant hematology specializing in translational research involving myeloproliferative neoplasms (MPNs) and progression to acute myeloid leukemia (AML), he evaluates rationale-based innovative therapeutics for patients with MPNs (myeloproliferative neoplasms) and AML. Dr. Mascarenhas is also the Principal Investigator (PI) of the clinical trials project under the Myeloproliferative Disorder Research Consortium, which is financed by the National Cancer Institute (MPD-RC).

He has acted as the PI or Study Chair for a number of investigator-initiated and industry-sponsored early and late phase clinical trials testing novel techniques for the treatment of MPNs and AML. In addition, he maintains a variety of administrative positions at Mount Sinai, such as Chair of the Leukemia Disease Management Team, Co-Chair of the Hematologic Malignancy Disease Focus Group, and full member of the Tisch Cancer Institute Protocol and Review Monitoring Committee.